The genetics of smoking in individuals with chronic obstructive pulmonary disease

Abstract

BackgroundSmoking is the principal modifiable environmental risk factor for chronic obstructive pulmonary disease (COPD) which affects 300 million people and is the 3rd leading cause of death worldwide. Most of the genetic studies of smoking have relied on self-reported smoking status which is vulnerable to reporting and recall bias. Using data from the Lung Health Study (LHS), we sought to identify genetic variants associated with quantitative smoking and cessation in individuals with mild to moderate COPD.MethodsThe LHS is a longitudinal multicenter study of mild-to-moderate COPD subjects who were all smokers at recruitment. We performed genome-wide association studies (GWASs) for salivary cotinine (n = 4024), exhaled carbon monoxide (eCO) (n = 2854), cigarettes per day (CPD) (n = 2706) and smoking cessation at year 5 follow-up (n = 717 quitters and 2175 smokers). The GWAS analyses were adjusted for age, gender, and genetic principal components.ResultsFor cotinine levels, SNPs near UGT2B10 gene achieved genome-wide significance (i.e. P < 5 × 10− 8) with top SNP rs10023464, P = 1.27 × 10− 11. For eCO levels, one significant SNP was identified which mapped to the CHRNA3 gene (rs12914385, P = 2.38 × 10− 8). A borderline region mapping to KCNMA1 gene was associated with smoking cessation (rs207675, P = 5.95 × 10− 8). Of the identified loci, only the CHRNA3/5 locus showed significant associations with lung function but only in heavy smokers. No regions met genome-wide significance for CPD.ConclusionThe study demonstrates that using objective measures of smoking such as eCO and/or salivary cotinine can more precisely capture the genetic contribution to multiple aspects of smoking behaviour. The KCNMA1 gene association with smoking cessation may represent a potential therapeutic target and warrants further studies.Trial registrationThe Lung Health Study ClinicalTrials.gov Identifier: NCT00000568. Date of registration: October 28, 1999.Electronic supplementary materialThe online version of this article (10.1186/s12931-018-0762-7) contains supplementary material, which is available to authorized users.

Assessing pleiotropy and mediation in genetic loci associated with chronic obstructive pulmonary disease

“…Previous studies have presented contradictory evidence of these explanations (Obeidat et al, 2018;Siedlinski et al, 2013;Vanderweele et al, 2012;Wilk et al, 2012;Zhang et al, 2017). While there is evidence of association between CHRNA5 and lung function in neversmokers (Wilk et al, 2012), suggesting an independent effect on lung function, recent analyses have found no association of this region with lung function or lung cancer in never-smokers (Obeidat et al, 2018;Wang, Broderick, Matakidou, Eisen, & Houlston, 2011). Likewise, previous meditation analyses in this region have found both a direct effect (Siedlinski et al, 2013) and no direct effect (Vanderweele et al, 2012) of the CHRNA5 genotype on airflow obstruction.…”

“…There are two possible explanations for this finding: (a) the smoking measurement used (average cigarettes smoked per day) does not accurately capture the pathological effects of smoking and the observed association of rs17486278 to FEV 1 /FVC is a result of residual confounding; or (b) independent of smoking, genotype at rs17486278 affects airflow limitation. Previous studies have presented contradictory evidence of these explanations (Obeidat et al, 2018;Siedlinski et al, 2013;Vanderweele et al, 2012;Wilk et al, 2012;Zhang et al, 2017). While there is evidence of association between CHRNA5 and lung function in neversmokers (Wilk et al, 2012), suggesting an independent effect on lung function, recent analyses have found no association of this region with lung function or lung cancer in never-smokers (Obeidat et al, 2018;Wang, Broderick, Matakidou, Eisen, & Houlston, 2011).…”

“…Previous studies have presented contradictory evidence of these explanations (Obeidat et al, 2018;Siedlinski et al, 2013;Vanderweele et al, 2012;Wilk et al, 2012;Zhang et al, 2017). Although the association of the 15q25.1 locus (which includes genes coding for nicotinic acetylcholine receptors) with nicotine dependence is indisputable, evidence for its independent association with airflow obstruction is variable.…”

“…Moreover, available measures of smoking behaviors (cigarettes smoked per day and current smoking status) may not completely capture the toxic effects of tobacco inhalation and recent work suggests objective biomarkers of smoking (e.g., exhaled carbon monoxide or cotinine) can more accurately capture smoking behavior (Obeidat et al, 2018). However, there are a few limitations of this dataset.…”

“…Participants may not have reported changes in smoking behaviors over their lifetime, potentially resulting in residual confounding that could bias reported results. Moreover, available measures of smoking behaviors (cigarettes smoked per day and current smoking status) may not completely capture the toxic effects of tobacco inhalation and recent work suggests objective biomarkers of smoking (e.g., exhaled carbon monoxide or cotinine) can more accurately capture smoking behavior (Obeidat et al, 2018). These measures were not available in the COPDGene study.…”